Etoposide and teniposide are semisynthetic podophyllotoxin derivatives that are in clinical usage as anticancer drugs FIG. 1 (Chen. Y. Z.; Wang. Y. G.; Tian, X.; Li, J. X. Curr. Sci 1990, 59, 517; Wang, J. Z.; Tian, X.; Tsumura, H.; Shimura, K.; Ito, H. Anti-cancer Drug Design, 1993, 8, 193).
It is believed that analogues of 4′-demethyl epipodophyllotoxin exert their antitumour activity through stabilization of a cleavable complex between DNA and type-II DNA topoisomerase, this leads ultimately to inhibition of DNA catenation activity and produces single and double strand breaks (Satio, H.; Yoshikawa, H.; Nishimura, Y.; Kondo, S.; Takeuchi, T.; Umezawa, H. Chem Pharm. Bull. 1986, 34, 3733; Chen, Y. Z.; Wang, Y. G.; Li, J. X.; Tian, X.; Jia. Z. P.; Zhang, Z. Y. Life Sci. 1989, 45, 2569).
A number of studies have been carried out on the structural modification of glycoside by amino substituents that has improved the inhibitory activity on human DNA topoisomerase-II as well as stronger activity in causing cellular protein length DNA breakage (Lee, K. H.; Imakura, Y.; Haruna, M.; Beers, S. A.; Thurston, L. S.; Dai, H. J.; Chen, C. H.; Liu, S. Y.; Cheng, Y. C. J. Nat. Prod. 1989, 52, 606; Liu, S. Y.; Hawang, B. D.; Haruna, M.; Imakura, Y.; Lee, K. H.; Cheng, Y. C. Mol. Pharmacol. 1989, 36, 8; Lee, K, H.; Beers, S. A.; Mori, M.; Wang, Z. Q.; Kuo, Y. H.; Li, L.; Liu, S. Y.; Cheng, Y. C.; J. Med. Chem. 1990, 33, 1364; Kamal, A.; Gayatri, N. L.; Reddy, D. R.; Reddy, P, S. M. M.; Arifuddin, M.; Dastidar, S. G.; Kondapi, M. A.; Rajkumar M. Bioorg. Med. Chem. 2005, 13, 6218; Kamal, A.; Kumar, B. A.; Arifuddin, M.; Dastidar, S. G. Bioorg. Med. Chem. 2003, 11, 5135).
A number of studies have been carried out on the structural modification of podophyllotoxin. Itokawa and Takeya made an important contribution to the field by demonstrating that greatly simplified 4-Aza-2,3-didehydropodophyllotoxins retain a most of the cytotoxicity associated with the parent lignan (Hitotsuyanagi, Y.; Kobayashi, M.; Fukuyo, M.; Takeya, K.; Itokawa, H.
A facile synthesis of the 4-Aza-analogs of 1-arylnaphthalene lignans —Chinensin, justicidin B, and Taiwanin C. Tetrahedron Lett. 1997, 38, 8295-8296; Hitotsuyanagi, Y.; Fukuyo, M.; Tsuda, K.; Kobayashi, M.; Ozeki, A.; Itokawa, H.; Takeya, K. 4-Aza-2,3-dehydro-4-deoxypodophyllotoxins: Simple Aza-podophyllotoxin analogues possessing potent cytotoxicity. Bioorg. Med. Chem. Lett. 2000, 10, 315-317). In this context a large number of 4-Aza-2,3-didehydro podophyllotoxins derivatives have been synthesized and investigated for their antitumour activity.
